tbuckley/cabot-search huggingface dataset:
JS03.5.A Pediatric Neurofibromatosis type 1- associated Malignant Peripheral Nerve Sheath Tumors: a national experience
Authors: E M Silva, S Nunes, I Luz, U Mohanlal, J Passos
Journal: Neuro-Oncology (2022)

Abstract Background Malignant peripheral nerve sheath tumors (MPNST) are rare soft tissue sarcomas and although less that 10% occur in the pediatric age, they are the most feared complication in the follow-up of Neurofibromatosis Type 1 (NF1) patients. NF1-children tend to have larger tumors and worse prognosis than non-NF1 patients. There is a lack of data regarding MPNST in pediatric populations with NF1, and the present work aims to characterize a Portuguese population of pediatric NF1 patients who developed a MPNST. Material and Methods Retrospective analysis of all NF1-pediatric patients diagnosed with MPNST between 2000 to 2021, from three centers in Portugal. Patient characteristics, treatment modalities and clinical outcomes were reviewed. Results 12 patients (6 males and 6 females) met the inclusion criteria. 7 had no family history of NF1. Median age at diagnosis was 14.1 years (range 10-18). 5 had been diagnosed previously with Plexiform Neurofibroma and were treated with selumetinib (2) and partial surgery (2). MPNSTs were mostly located in the retroperitoneum (7) and in the proximal lower limbs (2). Only 1 patient had a resectable tumor at diagnosis and 3 patients had metastatic disease. In the FDG-PET scan of evaluated patients (7), the mean maximum standardized uptake value of the main lesion was 6 (range 3.6-9.7).Neoadjuvant ifosfamide plus doxorubicin chemotherapy was used in 4 patients. The median overall survival in this population was 10.3 months (95% CI 0.1-20.6) 2 patients remain alive. Conclusion The prognosis of MPNSTs in NF1 pediatric patients is very poor. In a subset of patients, MPNSTs develop from known Plexiform Neurofibromas. Current surveillance ant treatment protocols need to be improved.
P10.22.A Prognostic role of<i>TCF7L2</i> in glioblastoma
Authors: R Radu, G E D Petrescu, R Ionita, A Gafencu, F Brehar, R M Gorgan
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma is the most common and devastating brain cancer and despite maximal surgical resection, chemotherapy and radiotherapy, the five-year survival rate is less than 7%. The TCF7L2 gene encodes transcription factor 7-like 2, a main effector of Wnt/β-Catenin signaling pathway involved in cancer development and progression. Aberrant activation of the TCF7L2 gene is one of the primary events in tumorigenesis by maintaining stem-cell characteristics, however its role in glioblastoma is poorly studied. Material and Methods The expression of TCF7L2 was analyzed by qRT-PCR in a series of consecutive glioblastoma samples from patients that underwent surgical resection. Secondary or recurrent glioblastomas were excluded from the analysis. All patients underwent radio- and chemotherapy according to the protocol. Housekeeping gene RPL13 was used as reference gene. The 2-ΔCT method was used to calculate the relative expression of TCF7L2 to the reference gene. Results A total of 49 glioblastoma samples were included in the study. The mean survival period was 58.2 weeks. The median value of TCF7L2 expression was used as a cut-off point for the survival analysis. There were no statistically significant differences regarding the clinical and histopathological factors between the groups with low and high expression of TCF7L2. By using the Kaplan-Meier analysis, we observed that patients with overexpression of TCF7L2 had a decreased survival rate compared to patients with low levels of TCF7L2 (38.8 weeks vs. 77.34 weeks, p = 0.001). Conclusion These results demonstrate that glioblastoma patients with high levels of TCF7L2 have a poorer survival rate and TCF7L2 might be a useful prognostic factor for these patients. However, further studies are needed to elucidate the mechanisms through which TCF7L2 affects the prognosis and its implication as a possible therapeutic target. This work was supported by an ERA PerMed grant - ERAPERMED2018-270 (PerProGlio).
P11.30.A Stereotactic Radiosurgery (SRS) for brain metastases in breast cancer: An evaluation of outcomes at a UK tertiary centre
Authors: P Abdul Haris, L Brazil, K Blythe, K Chia, S Hassan, T Loganathan, D Smith, A Swampillai, O Al-Salihi
Journal: Neuro-Oncology (2022)

Abstract Background Brain metastases (BM) occur in approximately 10-30% of patients with breast cancer (BC). Patients with advanced breast cancer are living longer, and the incidence of BM are increasing. Stereotactic Radiosurgery (SRS) has emerged as a strategy to treat BM. We evaluated the outcomes and potential prognostic factors of patients with BM treated with SRS. Material and Methods Retrospective review of patients treated with linac-based SRS for BM from BC in a single tertiary centre between August 2017-September 2021. Overall survival (OS), intracranial progression-free survival (IPFS), and prognostic factors were evaluated using Kaplan-Meier analysis, log-rank test, and Cox proportional-hazards model. Results 76 patients were included in the analysis. Out of these, 56 had first-line local treatment with SRS, either as primary (n=34) or adjuvant to surgery (n=22). Median age was 58 years old (range 37-86), and 88% had PS 0/1. One-year survival rate was 56%. Median OS and IPFS from SRS was 16 months (95% CI 8-24) and 7 months (95% CI 2-12), respectively. However, there were significant differences in OS (p&amp;lt;0.001) and IPFS (p=0.001) based on molecular subtypes. Patients with triple-negative breast cancer (TNBC) (n=14) had median OS of 7 months (95% CI 2-12), ER+/HER2- (n=22) median OS of 22 months, ER-/HER2+ (n=8) median OS of 4 months (95% CI 0-9), and ER+/HER2+ (n=11) median OS of 36 months. Similar trend was seen with IPFS. Patients with progressive extracranial disease compared to stable disease had shorter median OS (4 months vs 23 months, HR 2.4, p=0.01) and median IPFS (4 months vs 13 months, HR 2, p=0.03). Age ≥65 years was associated with shorter median OS (4 vs 23 months, HR 2.3, p=0.02). Patients with ≥4 brain metastases had shorter IPFS (4 months vs 11 months, HR 2.4, p=0.012), but no significant difference in OS. Volume of metastases did not affect outcome in this series. 30% of patients progressed intracranially after first-line SRS. 94 % had out-of-field recurrences, and 6% in-field recurrences. 59% had further SRS, 12 % WBRT, 6% surgery, and 23% had no further local treatment. 26 patients had second-line local treatment with SRS after first-line SRS (n=9), WBRT (n=9), or surgery +/- WBRT (n=8). There were no significant differences in outcome based on the modality of first-line local treatment. Conclusion SRS is an effective treatment for BM from BC. There were significant differences in survival based on age, molecular subtypes, and extracranial disease status.
P11.29.B Risk factors associated with the presence of brain metastasis at the moment of diagnosis in non-small cell lung cancer patients. Retrospective case series
Authors: C M Martín-Abreu, H Fariña-Jerónimo, J Plata-Bello
Journal: Neuro-Oncology (2022)

Abstract Background Lung cancer is the second most frequent neoplasm worldwide and the leading cause of cancer death in both sexes. Furthermore, it is the most common origin of brain metastases. The aim of this study is to identify clinical, histological, and molecular variables associated with a higher risk of presenting brain metastases at the moment of diagnosis in patients with lung cancer. Material and Methods A single-center retrospective case series analysis of patients with a new diagnosis of lung cancer (from January 2015 to December 2018) was performed. A total of 723 total patients with a new diagnosis of non-small cell lung cancer (NSCLC) were identified. Only patients with a brain imaging study at the time of diagnosis were included in the analysis. Non-parametric statistical tests were used to compare patients with or without metastases at the moment of diagnosis. A uni- and multivariate analysis were performed to identify risk factors associated with the presence of brain metastases at NSCLC diagnosis. Statistical significance was considered when p&amp;lt;0.05. Results We included 135 patients with a new diagnosis of lung cancer and with brain imaging study at the time of diagnosis (mean age at diagnosis of 64.69 years [SD= 10.34]; 71.9% men). The most common histology was adenocarcinoma (67.1%) followed by squamous carcinoma (25.2%). Brain metastases were present in 40% of patients at diagnosis. No significant differences in clinical, histological and molecular variables was identified between patients with or without brain metastases. In any case, as expected, the survival analysis showed that brain metastasis at diagnosis was associated with a worse overall survival (Log-Rank test, p&amp;lt;0.01).The univariate analysis showed that presenting neurological symptoms (OR=19.5, p&amp;lt;0.0001 CI [7.895-47.65]), histology of adenocarcinoma (OR= 2.113, p&amp;lt;0.014 CI [1.160-3.849]) and the presence of visceral metastases (OR= 14.444, p&amp;lt;0.0001 CI [6.161-33.86]) were associated to the presence of brain metastases at diagnosis. The presence of metastases limited to the thorax (OR= 0.019, p&amp;lt;0.001 CI [0.003-0.146] was associated to be free of brain metastasis at NSCLC diagnosis. However, only neurological symptoms (OR= 20.290, p&amp;lt;0.0001 CI [4.953-83.118]), presenting visceral metastases (OR= 4.451, p&amp;lt;0.010 CI [1.458-13.777]) and/or metastases limited to the thorax (OR= 0.066, p&amp;lt;0.024 CI [0.006-0.010]) reached statistical significance in the multivariate analysis. Conclusion Neurological symptoms and the presence of visceral metastases are independent predictors or presenting brain metastasis at the moment of diagnosis in lung cancer patients. On the other hand, the presence of lung cancer disease confined in the thoracic cavity is associated with a lower risk to present brain metastasis
JS08.6.A A connectivity signature for glioblastoma
Authors: D C Hoffmann, L Hai, R Wagener, H Mandelbaum, R Xie, D Hausmann, D Dominguez Azorín, S Weil, P Sievers, G Cebulla, J Ito, U Warnken, V Venkataramani, K Ernst, D Reibold, R Will, M L Suvà, C Herold-Mende, F Sahm, F Winkler, M Schlesner, W Wick, T Kessler
Journal: Neuro-Oncology (2022)

Abstract Background Tumor cell extensions called tumor microtubes (TMs) in glioma resemble neurites during neurodevelopment and connect glioma cells to a network that has considerable relevance for tumor progression and therapy resistance. The determination of interconnectivity in individual tumors has been challenging and the impact of tumor cell connectivity on patient survival remained unresolved so far. Material and Methods A connectivity signature was derived by single-cell RNA-sequencing (scRNA-Seq) of highly and lowly connected cells obtained from an SR101 dye transfer xenograft model of primary glioblastoma (GB). The signature was validated in different in vitro models of cell-to-cell connectivity and could be translated to GB clinical specimens. Results 34 of 40 connectivity genes were related to neurogenesis, neural tube development or glioma progression, including the TM-network-relevant GAP43 gene. Astrocytic-like and mesenchymal-like GB cells had the highest connectivity signature scores in scRNA-Seq data of patient-derived xenografts and patient samples. In 230 human GBs, high connectivity correlated with the mesenchymal expression subtype, TP53 wildtype, and with dismal patient survival. CHI3L1 was identified and validated as a robust molecular marker of connectivity with a functional relevance. Conclusion The connectivity signature gives novel insights into brain tumor biology, provides a proof-of-principle that tumor cell connectivity is relevant for patients’ prognosis, and serves as a robust biomarker that can be used for future clinical trials
P15.05.A Prediction of response to lomustine-based chemotherapy in glioma patients at relapse using MRI and FET PET
Authors: M M Wollring, J Werner, E K Bauer, C Tscherpel, P Lohmann, C Kabbasch, R Goldbrunner, G R Fink, K J Langen, N Galldiks
Journal: Neuro-Oncology (2022)

Abstract Background This study evaluates O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET and contrast-enhanced MRI for early response assessment in glioma patients at relapse treated with lomustine-based chemotherapy. Material and Methods Thirty-seven adult patients with WHO CNS Grade 3 or 4 gliomas at relapse (glioblastoma, 70%; median number of relapses, 1) were retrospectively identified. Besides MRI, serial FET PET scans were performed at baseline and early after chemotherapy initiation (median number of cycles, 2). Mean and maximum tumor-to-brain ratios (TBR), metabolic tumor volumes (MTV), the occurrence of distant hotspots with a mean TBR &amp;gt; 1.6 at follow-up, and dynamic parameters (i.e., time-to-peak and slope) were derived from all FET PET scans. Threshold values of PET parameters were defined using receiver operating characteristic analyses to predict progression-free survival (PFS) of ≥6 months and overall survival (OS) of ≥12 months. MRI response assessment was based on RANO criteria. The predictive value of FET PET parameters and RANO criteria were subsequently evaluated using univariate and multivariate survival estimates. Results After treatment initiation, the median follow-up time was 11 months (range, 3-71 months). Maximum TBR and MTV (threshold, ≤0%) and RANO criteria predicted a significantly longer PFS (all P&amp;lt;0.001) and OS (all P&amp;lt;0.03). At follow-up FET PET imaging, the occurrence of new distant hotspots (n≥1) predicted a worse outcome, with significantly shorter PFS (P=0.001) and OS (P&amp;lt;0.001). Dynamic PET parameters did not predict a significantly longer PFS or OS (P&amp;gt;0.05). Multivariate survival analyses revealed that new distant hotspots at follow-up had the highest level of significance to predict non-response (P=0.002; hazard ratio, 5.722), independent of RANO criteria, IDH mutation status, and O6-methylguanine-DNA-methyltransferase promoter methylation. Conclusion FET PET seems to be a powerful tool for identifying responders to lomustine-based chemotherapy early after treatment initiation.
P14.05.B Plasma-EV based liquid biopsy for precision medicine in the treatment of glioblastoma
Authors: S Faletti, E Zaccheroni, D Osti, M Del Bene, F DiMeco, G Pelicci
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma (GBM) is a devastating and protean brain tumor. Diagnosis and molecular characterization rely on magnetic resonance imaging and brain biopsy which are challenged by low specificity/sensitivity and surgical risks. This hampers the longitudinal monitoring of patients with GBM, whose molecular dynamism ideally requires to refine the therapeutic plan in different disease stages. Extracellular vesicles (EVs) shed by GBM act as a reservoir of circulating biomarkers and can be easily collected through a blood sample, placing the rational to exploit them as a platform for liquid biopsy in GBM. Material and Methods We isolated EVs from 2ml of pre-operative platelet-free plasma by Size Exclusion Chromatography (SEC). EVs are characterized by (i) immunoblot and Fluorescent-Activated Cell Sorter (FACS) for the presence of EV markers; (ii) TEM for morphology and size; (iii) Nanoparticle Tracking Analysis (NTA) for size and concentration; (iv) RNAseq and ddPCR for EV-associated nucleic acid profiling. Results SEC allowed to define EV-enriched fractions expressing the EV-markers CD9, CD81, Flotillin1, lacking the non-EV marker Calnexin and depleted of the majority of plasma contaminants. EV quantification by NTA confirmed their enrichment in the plasma from GBM patients. EV-RNA length (&amp;lt; 200nt) and total yield (1-10ng among different samples) allowed a successful RNAseq library preparation for downstream identification of splicing isoforms, translocations, fused mRNAs, and expression level of GBM-specific transcripts. The ddPCR-based analysis of mutations and copy number alterations proved the ability of cell-derived EV-DNA to recapitulate the alterations of the parental cells. Although the yield of plasma-EV-DNA is low (around 1ng), this paves the way to optimize the isolation/analysis of plasma EV-DNA to permit tumor profiling. Conclusion Plasma-EV based liquid biopsy could implement the personalisation of GBM care for every timepoint of the disease course. Increased plasma-EV concentration is an effective biomarker for GBM presence and its measurement well suits with the clinical routine. EV-RNA/DNA mirror the genomic profile of parental tumor and their analysis could allow the identification of actionable molecular aberrations and the monitoring of GBM mutability during follow-up. Thus, the multilayered analysis of plasma-EV concentration and cargo could enable GBM early diagnosis and to monitor therapy response and the whole tumor evolution.
P11.58.A Case of a complex neurocutaneous syndrome characterized by extensive peripheral nerve sheath tumors and somatic ERBB2 mutation
Authors: M Barden, J Baehring
Journal: Neuro-Oncology (2022)

Abstract Schwannomatosis is a rare genetic tumor predisposition syndrome characterized by the presence of multiple non-intradermal schwannomas and the definitive absence of vestibular nerve involvement. Though considered benign, the burden of tumors can cause significant morbidity in the form of motor dysfunction and refractory neuropathic pain. Treatment is focused on mitigating these symptoms, which includes resection of offending tumors when feasible and anti-angiogenesis therapy with bevacizumab. Options for targeted medical therapies are lacking. Schwannomatosis is molecularly distinct from the other neurofibromatoses and by definition lacks constitutional mutations in NF1 and NF2. Instead, constitutional mutations in SMARCB1 or LZTR1 are often the “first hit” in tumorigenesis. Activating mutations in ERBB2 (also designated HER2) have been identified as oncogenic drivers in peripheral nerve sheath tumors in patients who lack these typical constitutional tumor suppressor gene mutations. Here we report a case of extensive peripheral nerve sheath tumors in the setting of apparent somatic mosaicism of an ERBB2 mutation. A 48-year-old man with history of chronic back pain presented with diffuse enlarging soft tissues masses primarily involving the left neck and occiput. Examination revealed areas of cutaneous heterogeneous hyperpigmentation, decreased muscle bulk and dorsiflexor weakness in the bilateral lower extremities, and steppage gait. Neuroimaging showed extensive T2 hyperintense, mildly enhancing masses within the bilateral thoracic and lumbar spine neuroforamina, intercostal nerves, paraspinal musculature, and lumbosacral plexus. Tissue from two separate tumor sites was morphologically consistent with schwannoma with some features of neurofibroma. Immunohistochemistry revealed partial loss of staining for SMARCB1. Whole exome sequencing (WES) on blood and tumor tissue did not show pathogenic germline or somatic variants for NF1, NF2, SMARCB1, LZTR1, or an array of tumor predisposition syndromes. WES on tumor tissue from both sites however did reveal a somatic ERBB2 variant (p.D769Y), suggesting mosaicism. ERBB2 D769Y has previously been classified as an activating mutation that confers sensitivity to some small molecule receptor tyrosine kinase inhibitors. Patients with ERRB2-mutated peripheral nerve sheath tumors may have broader therapeutic options in the variety of available tyrosine kinase inhibitors studied in other cancers.
P01.07.A Neurocognitive outcomes after proton beam therapy for skull base tumours
Authors: S Gaito, E Hwang, M Aznar, A France, P Sitch, A Crellin, A L Holtsman, S Pan, G Whitfield, E Smith
Journal: Neuro-Oncology (2022)

Abstract Background Evidence suggests that Proton Beam Therapy (PBT) may lessen the risk of neurocognitive decline (NCD) by reducing the dose to the normal brain as compared to conventional photon radiotherapy (XRT). We report the incidence of moderate-severe (Grade ≥3) NCD in adults treated for skull base chordomas and chondrosarcomas within the United Kingdom’s Proton Overseas Programme (POP). Material and Methods Baseline (pre-PBT) and follow-up clinical outcomes data were prospectively collected as part of a national PBT-outcomes registry, which started in 2008 . This registry is curated by a dedicated Proton Clinical Outcomes Unit. Specifically, late toxicities ≥G3 as per CTCAE (Common Terminology Criteria for Adverse Events) v4.0 definition, occurring later than 90 days after treatment completion, were recorded. This study focuses on the incidence of memory impairment (MI) in the adult (≥25 y) cohort. Results Between 2008-2018, 141 adult patients were treated for skull base chordomas (77 patients, 54.6%) and chondrosarcomas (64 patients, 45.4%) via the POP (the majority -62.8%- treated at the University of Florida PBT Institute). Median age at treatment was 51 years (range 26-77). Median prescription dose was 73.8 GyRBE (70-75.6), with a median dose per fraction of 1.8 Gy (1.2-2.1). Of note, the median dose for chondrosarcomas was 70.2 GyRBE (70-75.6), whereas the median dose for chordomas was 73.8 GyRBE (72-75.6). Median follow up was 39 months (0-138). On clinical assessment, 4 patients (2 chordomas, 2 chondrosarcomas) were reported with G3 MI after a median time of 43 months (27-49). None of them had impaired memory at baseline, nor relevant neurological comorbidities. Median age of those who developed G3 MI was 63 y (39-70). Median prescription dose was 72.9 GyRBE (70-73.8). Plans were available for 3 of these 4 patients. Relevant dose statistics to hippocampi and temporal lobes were extracted. Dmean to the omo- and contralateral hippocampi in these 3 patient plans were: patient 1) 33.7 and 11.6 GyRBE; patient 2) 28.1 and 24.4 Gy; patient 3) 8.7 and 8.2 GyRBE, respectively. V20 to the omo- and contralateral temporal lobes in the same patients were: patient 1) 47% and 10%; patient 2) 29% and 28.7%; patient 3) 30% and 28%, respectively. Suggested constraints for these structures are: Dmean &amp;lt; 20 Gy to the hippocampi and V20Gy &amp;lt;10% to the temporal lobes. Conclusion Our results indicate that adult patients undergoing high dose radiation for radioresistant tumours may experience detrimental effects on memory. Neurocognitive baseline and follow-up assessment is not routinely performed in this age group but might be appropriate to explore which domains of cognitive function are mainly affected. Larger cohorts are warranted to establish predictive factors and better understand dose volume effect of brain structures and neurocognitive sequelae.